Factors Influencing Aging

Chapter 4: Cellular Biology This chapter explores altered cellular and tissue biology, focusing on cellular adaptation, injury, manifestations of cellular injury, cellular death, aging, and the various types of cell death such as necrosis and apoptosis. Cellular adaptation allows cells to respond to physiological and pathological conditions, but severe or prolonged stressors can lead to cellular injury or death. Common sources of cell injury include lack of oxygen, free radicals, infections, inflammation, and metabolic derangements. Cellular aging also contributes to changes in structure and function. Bullet points Necrosis ● Dense clumping of nuclear material and disruption of membranes indicate irreversible injury ● Necrosis is followed by leakage of necrotic cell contents into surrounding spaces, triggering an inflammatory response ● In later stages of necrosis, karyolysis (enzymatic hydrolysis of nuclear chromatin) occurs ● Pyknosis is the shrinking of the nucleus into a small, dense mass of genetic material ● Karyorrhexis is the fragmentation of the nucleus into small particles or "nuclear dust" ● Major forms of necrosis include coagulative, liquefactive, caseous, fatty, and gangrenous ● Coagulative necrosis results from protein denaturation and is seen in infarcts ● Liquefactive necrosis occurs in the brain due to ischemic injury and digestion of brain cells ● Caseous necrosis is common in pulmonary tuberculosis and involves granulomatous inflammation ● Fatty necrosis is caused by lipases and the formation of soaps from free fatty acids Gangrenous necrosis ● Tissue death resulting from severe hypoxic injury ● Commonly caused by blockage of major arterial vessels ● Particularly common in the lower leg with compromised circulation ● Bacterial invasion can lead to gangrenous necrosis in hypoxic conditions ● Dry gangrene results from coagulative necrosis and is characterized by dry and shriveled skin ● Wet gangrene is more lethal and develops from necrotizing bacterial infections ● Causes affected tissues to become cold, swollen, black, and foul odor ● Can also affect internal organs ● Gas gangrene is a type of wet gangrene caused by Clostridium spp. infection ● Rapidly progressive and can lead to death if left untreated Apoptosis ● Distinct type of cell death different from necrosis ● Active process of cellular self-destruction ● Implicated in both normal and pathologic tissue changes ● Occurs as a part of normal physiologic processes to maintain cell balance ● Caused by severe cell injury or accumulation of misfolded proteins ● Linked to degenerative diseases of the CNS and other organs Unfolded Protein Response in ER ● When proteins in the endoplasmic reticulum (ER) misfold, it triggers the unfolded protein response ● If restoration of the protein fails, the cell undergoes apoptosis or programmed cell death ● Examples of diseases caused by misfolding of proteins include Alzheimer's disease Infections ● Apoptosis can be a result of the host's immune response to viral infections ● Cytotoxic T lymphocytes induce apoptosis to eliminate infected cells, but it can lead to tissue damage ● Excessive apoptosis can occur in tumor-related diseases and organ transplant rejection Obstruction in tissue ducts ● Obstruction of blood flow to an organ can result in pathological atrophy ● Excessive or insufficient apoptosis is known as dysregulated apoptosis ● A low rate of apoptosis can promote the survival of abnormal cells and increase the risk of cancer ● Defective apoptosis can lead to autoimmune disorders Initiation of apoptosis ● Apoptosis requires tightly regulated cell signaling ● Caspases, a type of protease enzyme, play a key role in triggering proteolytic activity and initiating apoptosis ● Activated caspases cleave other proteins, initiating a series of reactions known as the "suicide" cascade Mechanisms of apoptosis ● There are two main pathways of apoptosis: the mitochondrial (intrinsic) pathway and the death receptor (extrinsic) pathway ● Cells undergoing apoptosis release chemical factors to recruit phagocytes for clearance of cellular remnants Autophagy ● Autophagy is a self-destructive process that delivers cytoplasmic contents to the lysosome for degradation ● It acts as a recycling factory and a survival mechanism ● Macroautophagy is the most common form of autophagy Types of Autophagy ● Macroautophagy: The formation of an autophagic vacuole called an autophagosome, which engulfs intracellular contents and fuses with a lysosome to form an autophagolysosome, where degradation occurs. ● Microautophagy: The inward invagination of the lysosomal membrane to directly deliver cargo for degradation. ● Chaperone-mediated autophagy: Proteins dependent on chaperones facilitate transportation of cargo across the lysosomal membrane. Roles and Regulation of Autophagy ● Initiated in response to starvation or nutrient deprivation to maintain cellular metabolism. ● Removes damaged organelles under stress conditions, enhancing survival. ● Implicated in diseases such as cancer, heart disease, neurodegenerative diseases, inflammation, and infection. ● Autophagy genes activated by cellular stresses create vacuoles in which organelles are degraded and recycled as nutrients for the cell. Importance of Autophagy ● May hold promise for developing new therapeutic strategies in treating diseases. ● Suggested to be an immune defense mechanism against intracellular pathogens. ● Inefficient autophagy in aging individuals leads to the accumulation of harmful agents, contributing to cell damage and diseases such as dementia and cancer. Factors Influencing Aging ● Aging is a normal, universal, and inevitable process associated with a gradual loss of homeostatic mechanisms. ● Multiple factors including genetics, inflammation, oxidative stress, and metabolism contribute to aging. ● Research explores genetic signatures of exceptional longevity, epigenetic mechanisms, intrauterine environment, and lifestyle factors. ● Studies focus on the impact of insulin and insulin-like growth factor 1 (IGF1) signaling, mitochondrial dysfunction, and inflammation on aging. Inflammatory response and aging ● The inflammatory microenvironment can lead to chronic disease, frailty, and decreased lifespan in older adults ● Coagulation, a part of the inflammatory response, may lead to thickening (hypercoagulable) blood and clot formation in arteries and veins Role of microbiota and immunity in aging ● The microbiota plays a role in the induction of the immune system ● Adaptive immunity declines with age, while innate immunity may result in mild hyperactivity Senescence and its impact ● Senescence is a process where cells undergo permanent proliferative arrest in response to stressors ● Senescent cells accumulate over time and contribute to tissue dysfunction Diet and aging ● Diet is believed to play a major role in both the development and prevention of age-related diseases Understanding aging for healthy aging ● Understanding the physiology of aging supports public health efforts to promote healthy aging and delay vulnerability and frailty ● Extending lifespan is not the same as delaying aging; the goal is to extend a person's health span